Once established, human tumors are not rejected by the immune system, a state of functional tolerance which eventually proves fatal to the host (Smyth, M. J., et al., Nat. Immunol. 2, 293 (2001)). Evidence from murine models suggests that immunologic unresponsiveness may arise when tumor-associated antigens are presented by certain bone marrow-derived tolerogenic (tolerance-producing) antigen-presenting cells (APCs) (Sotomayor, E. M., et al., Blood, 98: 1070-1077 (2001); Doan, T., et al., Cancer Res., 60: 2810-2815 (2000)). Conversely, in the setting of tissue transplantation, it would be desirable to isolate and administer such tolerogenic APCs.
However, in humans and mammals other than mice, the identity of tolerogenic APCs, and the mechanisms they use to induce tolerance, remain elusive. Thus, in humans, “immature” myeloid dendritic cells (DCs) have been postulated to function as tolerizing APCs based on findings that these cells: (1) have a decreased ability to stimulate T cell responses in vitro (Reddy, A., et al., Blood, 90: 3640-3646 (1997); Jonuleit, H., et al., Eur. J. Immunol., 27: 3135-3142 (1997)); (2) may promote the function of immunosuppressive or “regulatory” T cells (Tregs) following prolonged co-incubation (Jonuleit, H., et al., Trends Immunol., 22: 394-400 (2001)); and (3) have the ability to abrogate antigen-specific T cell responses in vivo (Dhodapkar, M. V., et al., J. Exp. Med., 193: 233-238 (2001); see also U.S. Pat. Nos. 5,871,728 and 6,224,859). However, the molecular mechanism used by immature DCs or other putative tolerogenic APCs to suppress T cell responses is unclear.
Other findings indicate that maturation of DCs is not necessarily associated with abrogation of T cell suppression and/or tolerance (Albert, M. L., Nature Immunol., 2: 1010 (2001); Shortman, K. et al., Nature Immunol., 2: 988-989 (2001); T. Bankenstein and T. Schuler, Trends in Immunol., 23: 171-173 (2002)). Instead, there may be an as yet undefined signal that acts after T cells have received the signals of antigen presentation and co-stimulation from a fully mature APC which then diverts the T cells to activation or tolerance. In this model, the tolerogenic phenotype is independent of the maturation status of the APC (in fact, maturation enhances tolerance induction) and depends instead on an intrinsic attribute of the APC.
It would be desirable to prevent tolerogenic APCs from inducing tolerance where such tolerance is not therapeutically beneficial, as for example, at the site of a tumor or a tumor draining lymph node. Thus, it would be desirable to prevent the migration of tolerogenic APCs to sites, such as tumors, where they are detrimental, while still allowing for migration of non-tolerogenic (i.e., activating) APCs to these sites.